Human somatic cell genetic research is proposed to dissect and assign to chromosomes the different numbers and kinds of genes necessary for the final expression of enzymes and proteins as an approach to reducing to experimental dimensions of human development and metabolic disease. Using the somatic cell hybrid methodology, structural genes, post-translational modification genes, regulatory genes, subcellular localization genes, and assembly genes will be described that function in the biogenesis of enzymes and proteins. These studies will involve the genetic characterization of lysosomal enzymes, enzymes in amino acid metabolism, adenosine deaminase in purine metabolism, the immunoglobuins, and H1 histone proteins in chromatin assembly. These proteins were chosen since several genes are involved in their final expression and, when altered, abnormal development and severe inherited disease result. The genetic dissection and chromosome mapping of these essential enzymes and proteins will be studied using normal and enzyme-deficient human cultured cells in cell hybrid or heterokaryon combinations with either human or rodent cells. Enzyme-deficient fibroblasts to be used are associated with neurodegenerative diseases such as Tay-Sachs, Sandhoff-Jatzkewitz, metachromatic leukodystrophy, and GM1 gangliosidosis; with aminoacidopathies such as argininosuccinic aciduria, cystathionuria, and homocystinuria; and with immune diseases such as severe combined immunodeficiency disease and other immunoglobulin disorders. A genetic dissection and chromosome mapping of these disorders using somatic cell hybrids will provide a better molecular understanding of these often fatal diseases, what type of gene is abnormal, and how it relates to abnormal development. Such genetic information will undoubtedly aid in genetic counseling and prenatal diagnosis. Assignment of these genes will contribute to understanding the organization of the human genome as it relates to essential biological molecules, to human development, and to molecular disease.